Sounds are encoded by the cochlea in the timing of spikes in the auditory nerve. Auditory nerve fibers converge onto bushy cells in the cochlear nucleus, through synapses called "endbulbs of Held". This convergence leads to changes in the timing information passed on by bushy cells to higher auditory centers, which may affect sound localization and processing. Experiments have indicated that the timing of bushy cell spiking is greatly affected by the size of the endbulb synaptic current, which is subject to two major influences in vivo. First, endbulb synapses show considerable depression when activated at normal rates. Second, they are subject to a number of neuromodulatory systems. Both these influences can affect the information carried by bushy cells, but neither is well understood. The specific aims of this project are to determine (1) the dynamics and mechanisms of use-dependent changes in the endbulb synaptic current, (2) how the different components of the synaptic current control bushy cell timing, and (3) how neuromodulation changes these relationships. This work will be carried out using patch-clamp recordings of bushy cells in brain slices taken from mice and gerbils. The mechanisms of depression will be considered first, by testing the contributions of presynaptic vesicle depletion and postsynaptic receptor desensitization and saturation. In addition, an unusual form of depression at the endbulb will be examined, which has been proposed to involve reduced presynaptic calcium influx, but has never been directly tested. It will also be determined how depression could be mitigated by both facilitation and the activation of NMDA receptors. In addition, current- and dynamic-clamp studies will test whether delayed release during high levels of activity disrupts the precisely timed responses of bushy cells. Taken together these studies will provide important information about the mechanisms by which timing information is transformed by convergence of auditory nerve synapses during realistic activity. This work will examine the mechanisms used by cells in the cochlear nucleus to process sound information. It will also provide important insights into the functional role that different receptor types and neuromodulatory systems play in neuronal computation. This work may lead to improvements both in existing cochlear implants and in implants that stimulate the cochlear nucleus directly.